Amyloid diseases, such as Alzheimer's disease, Huntington's disease, and type II diabetes, are debilitating diseases resulting from cellularly processed protein agglomerates. Alzheimer's disease (AD) is the most common progressive dementing disorder characterized by deposition of amyloid-β peptide (Aβ) in the brain parenchyma. Aβ plaques are potent activators of both microglia and astrocytes, central nervous system (CNS)-resident immunocompetent cells that respond to cerebral amyloidosis by pro-inflammatory, chronic activation (Bussiere, T., et al., Morphological characterization of Thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive A-beta immunotherapy on their clearance. Am. I Pathol. 165: 987-995, 2004).
Studies have suggested that the Aβ-mediated inflammatory cascade not only affects clinical outcomes but also the extent of neuronal injury. Strategies aimed at manipulating this inflammatory cascade, including Aβ immunization (Chen, B., et al., Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32: 2682-2688, 2001; Ende, N., and I L Chen. Parkinson's disease mice and human umbilical cord blood I MecL 33: 173-180, 2002), non-steroidal anti-inflammatory drugs (NSAID) (Cole, G., et al. NSAID and Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal Models. Ann. N.Y. Acad ScL 1035: 68-84. 2004; Henning, R., et al. Human umbilical cord blood mononuclear cells for the treatment of acute myocardial infarction. Cell Transplant. 13: 729-7392004; Holcomb, L., et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med 4:97-100, 1998) and modulation of microglial activation (McGowan, E., et al. Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin I transgenes. Neuroblol. Dis. 6:231-244, 1999; Newman, M. B., et al. Human umbilical cord blood (HUCB) cells for central nervous system repair. Neurotoz Res. 5: 355-368, 2003; Roach, T., et al. Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Res. 1015: 161-168, 2004), are able to reduce AD-like pathology and improve behavioral impairment in Alzheimer's transgenic mouse models and, in some cases, reduce AD pathology in humans.
It was previously shown that the CD40-CD40 ligand (CD40L) interaction plays a critical role in Aβ-induced microglial activation (Tan et al., Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science, 286:2352-2355, 1999). Disruption of this signaling pathway reduces cerebral Aβ deposits in Tg2576 mice and improves cognitive deficits in PSAPP mice (Tan et al., CD40-CD40L interaction in Alzheimer's disease. Curr Opin Pharmacol, 2:445-451, 2002; Roach et al., Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Res, 1015:161-168, 2004). The implication of the CD40-CD40L interaction in AD-associated brain inflammatory processes is supported from studies demonstrating increased expression of CD40 and CD40L in and around the β-amyloid plaques characteristic of the AD brain (Togo, et al., Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases, Brain Res, 885:117-121, 2000; Calingasan, et al., Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol Aging, 23:31-39, 2002). Recently, Desideri and colleagues (Desideri G., et al., Enhanced soluble CD40 ligand and Alzheimer's disease: evidence of possible pathogenetic role. Neurobiol Aging, 29:348-356, 2007) reported that circulating soluble CD40L (sCD40L) levels are significantly increased in AD patients versus healthy elderly controls, further suggesting an important association between CD40-CD40L interactions and the pathogenesis of AD.
Human umbilical cord blood cells (HUCBC) have been shown to be antagonists of the pro-inflammatory T helper cell type 1 (Th1) response, as demonstrated in an animal model of stroke where HUCBC infusion promoted a strong T-helper 2 (Th2) response (Vendrame, M., et al., Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduced infarct volume. Stroke, 35:2390-2395, 2004). This modulation was correlated with reduced infarct volume and a rescue of behavioral deficits (Vendrame 2004). HUCBC infusion has also shown to be a therapeutic benefit in other neuroinflammatory conditions including multiple sclerosis, amyotrophic lateral sclerosis, neurodegenerative macular degeneration, and Parkinson's disease (Henning, R., et al. Human umbilical cord blood progenitor cells are attracted to infracted myocardium and significantly reduce myocardial infarction size. Cell Transplant. 15: 647-658, 2004; Garbuzaova-Davis S., et al., Maternal transplantation of human umbilical cord blood cells provides prenatal therapy in Sanfilippo type B mouse model. FASEB J., 20:485-487, 2006). In AD preclinical models, administration of these cells into PSAPP mice was associated with life extension, although high doses were administered (Ende, N. et al, Human umbilical cord blood cells ameliorate Alzheimer's disease in transgenic mice. J Med, 32:241-247, 2001).
Modulation of the inflammatory cascade by several diverse strategies including Aβ immunization, non-steroidal anti-inflammatory drug (NSAID) administration, and manipulation of microglial activation states have all been shown to reduce Alzheimer disease (AD)-like pathology, and cognitive deficits in AD transgenic mouse models. However, these treatments also possess strong side effects, for example an increased risk of bleeding associated with NSAID use. Therefore, a safer, efficacious AD treatment is needed.